Immunosuppressive agents find current use in two principal clinical circumstances: organ transplantation and auto-immune diseases. The latter are pathological conditions arising from immunological reactions injurious to the body's own constituents. Examples of such conditions include idiopathic thrombocytopenic purpura, auto-immune hemolytic anemia, acute glomerulonephritis, systemic lupus erythematosis, polyarteritis nodosa, rheumatoid arthritis, dermatomyositis, scleroderma and giant-cell arteritis.
The following drugs have been found clinically useful in modifying immunological processes:
1. Alkylating Agents
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (cyclophosphamide) PA0 p-di(2-chloroethyl)amino-L-phenylalanine (melphalan) PA0 6-mercaptopurine PA0 6-thioquanine PA0 5-fluorouracil PA0 5-bromodesoxyuridine PA0 6-(1-methyl-4-nitro-5-imidazolyl)mercaptopurine (azathioprine) PA0 4-aminofolic acid PA0 4-amino-10-methylfolic acid PA0 cortisone PA0 prednisone
2. Purine and Pyrimidine Analogues
3. Folid Acid Antagonists
4. Steroids
In addition to the compounds listed above, other compounds have been reported to have immunoregulatory activity. These include levamisole [Huskisson et al., Lancet 1, 393 (1976); Runge et al., Arth. and Rheum. 20, 1445 (1977)] and certain N-2-(6-hydroxybenzothiazolyl)-N'-phenylureas (Paget and Wikel, U.S. Pat. No. 3,932,434).
The compounds of the present invention are novel. However, certain [1]-benzothiopyrano[4,3-c]pyrazoles, lacking the 3-keto and 2-phenyl groups of the compounds of the present invention, are reported to be useful as non-estrogenic antifertility agents (Houlihan, U.S. Pat. No. 3,816,438) or as antibacterial agents (Wagener, U.S. Pat. No. 3,235,564). Other benzothiopyranopyrazoles of no known utility have also been reported in the literature [for review, see Schneller in "Advances in Heterocyclic Chemistry," Vol. 18, Katritzky and Boulton, eds., Academic Press, New York (1975), pp. 88-94]. Exemplary are 1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole and its 5,5-dioxide [Pagani and Maiorana, Chim. Ind. (Milan) 53, 469 (1971); Chem Abstr. 75, 48829c]; 2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazole and its tautomer [Pagani and Maiorana, op. cit.]; and 1-phenyl-1,2,3,5-tetrahydro[2]benzothiopyrano[4,3-c]pyrazol-3-one [Scrowston and Shaw, J. Chem. Soc. Perkin Trans., 749 (1976)]. The last named compound is an isomer of one of the compounds of the present invention.